New alkyl-piperidines



Tweak- United States Patent 3,153,046 r NEW ALKYL-PIPERIDINES KarlHoifmann, Binningen, and Ernst Snry, Basel, Switzerland, assignors toCiba Corporation, a corporation of Delaware No Drawing. Filed May 22,1961, Ser. No. 111,490 Claims priority, application Switzerland, May 20,1960,

. 5,818/ 60 11 Claims. (Cl. 260-2934) ."The present invention concernsdi-alkyl-piperidylmethanols of the formula in which Pi represents apiperidyl radical, R, and R alkyl radicals containing from 4 to. 16carbon atoms, and their acid addition salts and quaternary ammoniumsalts. R and K, may be different but they are preferably identical.

The piperidyl radical, which is connected with vthe radical of themolecule in positions 2,3 or 4 and preferably in position 3 or 4,,may besubstituted by lower alkyl groups in any position, for instance methyl,ethyl, propyl, butyl; especially it is substituted at the nitrogen atomby lower alkyl or hydroxyalkyl groups. Suitable substituents at thenitrogen are for instance methyl, ethyl or propyl, hydroxyethyl orhydroxypropyl.

For the present purpose quaternary ammonium salts areabove all loweralkyl-ammonium salts, the anion bei'ng selected from the groupconsisting of mineral acids, for instance hydrohalic acids, such ashydrochloric acid,

hydrobromic acid or hydroiodic acid, or sulfuric acid or of organicsulfonic acids, for instance lower alkyl sulfonic acids such as methaneor ethane sulfonic acid or aryl sulfonic acids, such as benzene sulfonicacid, p-toluene sulfonic acid, p-bromobenz'ene sulfonic acid.

The new compounds possess valuable properties. Inter alia they havefungicidal and especially antibacterial properties, for example againstMicr osporum audouini, Trichophyton interdigitalis and Staphylococcusaureus and they. act against tubercle bacilli and can therefore be usedas disinfectants, preservatives or medicaments for the treatmentof'bacterial infections, for example such as, have been caused by theabovementioned organisms.

3,153,046 Patented Get. 13,1964

ice

in which R, and R have the above meaning and Py represents anunsubstituted or lower alkyl substituted pyridyl radical, can be treatedwith a hydrogenating agent.

The hydrogenation can be carried out with an agent knownto be suitablefor hydrogenating a pyridine ring. Thus, for example, the hydrogenationis carried out with hydrogen in the presence of a catalyst of a metal ofthe eighth group of the Periodic System, preferably a noble metalcatalyst such as platinum or palladium, for example with platinum inglacial acetic acid or palladium carbon in alcohol or isopropanol, or inthe presence of cobalt or nickel (Raney or Rupe).

A secondary alkyl-piperidine compound obtained by the present processcan be converted into a tertiary compound in the known manner. It can,for example, by

. alkylated in the usual manner or converted into the correspondingtertiary hydroxyalkyl derivative, for example, by treatment with a1:2-alkylene oxide.

A tertiary amino compound obtained by the present process can bequaternated in the conventional manner, preferably with a reactive esterof a lower alkanol, such as an ester thereof with a mineral acid or anorganic sulfonic acid as mentioned above, for example a hydrohalic acid,sulfuric acid or an arylsulfonic acid.

Depending on the procedure used the new compounds are obtained in theform of their bases or salts. From the salts the free bases can beprepared in the known manner.

Reaction of a free base with an acid suitable for the Of special valueinthis respect are the compounds-of the formula v l 3 2) 5-n z) 511 113as well as their therapeutically useful acid addition salts andquaternary lower alkyl-ammonium salts which are distinguished also bytheir stability towards soap and sera. Special mention deservedi-octyl-3-piperidylmethadi-octyl-4-piperidylmethanol,di-decyl-Z-piperidyh methanol, di hexyl-3-piperidylmethanol,di-heXyl-4-piperidylm'ethanol, their acid addition salts and quaternaryammonium salts.

The new compounds are obtained by methods as such know-n, Thus an alkylpyridine of the formula preparation of therapeutically useful saltsyields salts, for example those of the hydrohalic acids, e.g.,hydrochloric or hydrobromic acid, perchloric acid, nitric or thiocyanicacid, or sulfuric acid, or phosphoric acid, or organic acids, such asformic acid, acetic acid, propionic acid, glycollic acid, lactic acid,pyruvic acid, oxalic acid, malonic acid, succinic acid, 'rnaleic acid,furnaric acid, malic acid, tartaric acid, citric acid, ascorbic acid,hydroxy maleic acid, dihydroxymaleic acid, benzoic'acid, phenylaceticacid, 4- aminobenzoic acid, 4-hydroxybenzoic acid, anthranilic acid,cinnarnic acid, mandelic acid, salicyclic acid, 4- aminosalicyclic acid,2-phenoxybenzoic acid, Z-acetoxybenzoic acid, methanesulfonic acid,ethanesulfonic acid, hydroxyethanesulfonic acid, benzeneorp-toluenesulfonic acid, naphthalenesulfoni'cacid, or sulfanilic acid.

The new'comp'oun'ds may containasymm-etrical carbon atoms so that they,are obtained in the form of racemate method, such as crystallization.-The individual racemates can be resolved into their optically activeantipodes by the conventional method.

The starting materials are known or can be made by as'such knownmethods.

The new compounds can be used in human. or" veterinary medicine asmedicaments in the form of pharmaceutical preparations containing themin admixture with a suitable vehicle or diluent. Suitable vehicles are,for example, substances that do not react with the new compounds, suchas Water, gelatine, lactose, starch, magnesium stearate, talc,vvegetable oils, benzyl alcohols, gums, polyalylene glycols, whitepetroleum, jelly, cholesteiol or other known medicinal, vehicles. Thepharmaceutical preparations may, be, for example, tablets, drages,powders, ointments, creams, suppositories or in liquid form solutions,suspensions or emulsions. They may be sterilized'and/or may containassistants such as preservatives, stabilizers, wettingagents oremulsifiers. They may further contain other therapeutically valuablesubstances.

The new compounds are also suitable as'disi nfectants or preservatives,for example for disinfecting the skin, for example the hands,instruments, underwear or the like, and also for disinfecting orpreserving victuals or feedingstuifs. They may be applied by themselvesor in admixture ina solution or emulsion and/or with other activeprinciples or inert substances, such as ointments, or in the form of drypowders.

The following examples illustrate the invention without restricting itsscope thereto.

Example 1 A solution of 98 grams of di-lauryl-3-pyridylmethanol in 400cc. of isopropanol is hydrogenated with the" aid of 5 grams of palladiumcarbon of strength as catalyst in an autoclave with hydrogen at 115 C.under a pressure of 100 atmospheres gauge until the pressure re.- mainsconstant. The catalyst ,is then filtered off, the solvent is evaporatedand the residue (95 grams) is distilled in a high vacuum.

Di-lauryl-B-piperidylmethanol boils at 231-240" C. under a pressure of0.12 mm. Hg or at 130-135 C. under a pressure of 11.5 microns (moleculardistillation apparatus). It corresponds to the formula lNH When theproduct is dissolved in methanol, treated with a calculated amount ofhydrochloric or acetic acid and evaported, the hydrochloride (M.P.=8486C.) and the acetate respectively is obtained.

The aforementioned starting material is prepared by adding a solution of30.2 grams of nicotinic acid ethyl ester in 250 cc. of toluene dropwiseat 30-50 C. to an ethereal solution of the Grignard compound preparedfrom 12.15 grams of magnesium and 131 grams of lauryl bromide andstirring the mixture for 4 hours at 60 C. under nitrogen. The Grignardcomplex is decomposed in a solution of ammonium chloride which is thenworked up in the usual manner, the whole is distilled in a high vacuumand the forerunnings are separated, whereupondi-lauryl-3-pyridylmethanol is obtained.

Instead of nicotinic acid ethyl ester it is possible to usenicotinicacid'rnethyl ester which boils at 235237 C. under 0.05 mm. Hgpressure.

I Example. 2 a A solution of 19.4 grams 0f di-lauryl-4-pyridyl-Di-hexadeoyl-3piperidylmethanoL i Example 3 The following compounds areprepared as described in Examples 1 and 2:

Di-deeyl-3-piperidyimethanoL. I

Di-butyl-ipiperidylmethanoi. Di-hexyl-4 piperidylmethanolDi-octyl-4-piperidylmethanoL Di-deeyli-pipcridylmethanolDi-hexadecyl-4-piperidylmethanol The starting materials to be useddescribed in Example 1:

Boilin Under Melting atC. mm.Hg atC Di-butyl-B-pyridylmethanol.Di-hexyl-3-pyridylmethanol Di-octyl-3-pyridylmethanoLDi-decyl-3-pyridy1meth anoi. Di-hexadecyl-3-pyridylmethanolDi-butyM-pwidylmethanoi Di-hexyl-d-pyridylmethanolDi-ootyl-4-pyridylmethanoL. Di-deeyl-4-pyridylmethanoLDi-hexadecyl-4-pyridylmethanol.-

Example 4 Whena mixture of a solution of 8 grams of di-lauryl-3-pyridylmethanol in 60 cc. of ethyl acetate and 2.7 grams (:2 cc.) ofdimethyl sulfate is left to itself for one hour, then evaporated todryness, the di-lauryl-3-pyridylmethanol-methosulfate formed isdissolved in cc. of methanol and the solution is hydrogenated with 0.5gram of platinum oxide under hydrogen at 25 C. under atmosphericpressure, di lauryl 3 (l-methyl-piperidiyl)-methanol of the formula '7 Fz5Cia-(I3C12H2s methanol in 100 cc. of methanol and 5 cc. of acetic acid7 is hydrogenated with the aid of 1.5 grams of platinum oxide ascatalyst with hydrogen under atmospheric pressure at 25 C. The catalystis filtered ofi, the solvent evaporated, the residue is renderedalkaline (pl-1:11)

extracted with ether, the ether solution is washed until neutral'andthen dried and the ether is distilled off. The residue is then distilledin a high vacuum to yield 16 with sodium hydroxide solution, theprecipitated oil is grams of -di-lauryl-4-piperidylmethanol of theformula is obtained which boils at 230-232 C. under a pressure of 0.09mm. Hg.

Example 5 i lauryl-3-(l-methyl-piperidyl)-methanol of the'formula N-OH;1e

v p 0113 crystallizes out; it melts at -86 C.

. 5 Example grams of ethylene oxide are added to a solution of 10 gramsof di-lauryl-3-piperidyl-methanol in 50 cc. of

methanol; The additive reaction is catalyzed by adding 1 cc. of N-aceticacid. The reaction mixture is kept overnight, evaporated to dryness andthe residue is disa.) tilled in a high vacuum, to yielddi-lauryl-3-(1-5-hydroxyethyl-piperidy1)-methanol of the formula OH 7 25l2- 12 25 What is claimed is:

1. A member selected from the group consisting of a compound of theformula wherein R stands for a member selected from the group consistingof hydrogen, lower alkyl and hydroxyalkyl and each of the letters It andm stands for one of the integers from 5 to 11, inclusive, and atherapeutically useful acid addition salt thereof and a quaternary loweralkyl ammonium salt thereof. 9 I 2. The compounddi-octyl-3-piperidyl-methanol.

3. The compound di-octyl-4-piperidyl-rnethanol.

4. The compound di-heXyl-3-piperidyl-methanol.

5. The compound di-hexyl-4-piperidyl-rnethanol.

References Cited in the file of this patent UNITED STATES PATENTSSperber et al Mar. 27, 1956 OTHER REFERENCES Winterfield et al.:Chemical Abstracts," vol. 29, page 7331 (1935).

Tilford et al.: Journ. Am. Chem. 800., vol. 70, pages 4001-08 (1948).

Sperber et al.: Journ. Am. Chem. Soc, vol. 887- (1949).

McCarty et al.: Journ. Amer. Chem. Soc, vol. 79, pages 472-480 (1957).

Parkin et al.: "Journ. Am. Chem. 800., vol. 80, 2899- 2902 (1958).

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA
 2. THE COMPOUND DI-OCTYL-3-PIPERIDYL-METHANOL.
 7. ATHERAPEUTICALLY USEFUL ACID ADDITION SALT OF THE COMPOUND OF CLAIM 2.